Congestive Heart Failure: Fifty Years of Progress

Eugene Braunwald and Michael R. BristowCongestive Heart Failure: Fifty Years of Progress

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Congestive Heart Failure: Fifty Years of ProgressEugene Braunwald, MD; Michael R. Bristow, MD, PhD

Volume 1 ofCirculation provides an excellent snapshotof the understanding of the mechanisms and treatment

of heart failure a half century ago. During that era, circulatorypathophysiology was at the center of investigative attention.For example, Tinsley Harrison and his group divided heartfailure into “primary disorders of filling and primary disor-ders of emptying,”1 a forerunner of our current terms diastolicand systolic heart failure. The great Swedish clinical physi-ologist Gustav Nylin used32P-labeled red blood cells formeasuring cardiac output and cardiothoracic blood volume bythe indicator-dilution method in normal subjects and inpatients with heart failure.2 Andre Cournand’s group definedthe pathophysiology of heart failure secondary to cor pulmo-nale, distinguished it from left ventricular failure, and com-pared the acute hemodynamic effects of digoxin in these 2conditions.3 In a seminal paper, Raab and Lepeschkin ex-tracted sympathin from the heart and established norepineph-rine as the cardiac adrenergic neurotransmitter.4 In one of theearliest efforts to manage patients with chronic congestiveheart failure on an outpatient basis, Vander Veer and col-leagues demonstrated the effectiveness and tolerability of anoral form of the widely used parenteral diuretic mercuhydrin.5

Myocardial FunctionIn the 1950s, the role of hypertrophy in the heart’s adaptationto hemodynamic overload was examined. After Laplace’s lawwas applied to the heart and permitted the calculation of wallstress in the human heart,6 it became clear that myocardialhypertrophy prevents excessive elevation of wall stress con-sequent to hemodynamic overload.7,8 In the 1960s, there wasa lively debate about the mechanism of heart failure second-ary to pressure overload. The question was framed as follows:“Does failure of the ventricle as a pump occur in the presenceof (an) inadequate contractile mass while the contractilefunction of each unit (of myocardium) is normal or evensupernormal, or does failure result as a consequence of adepression of contractility of the myocardium that is notcompensated for by the increase in muscle mass?”9 The latterposition was supported by the demonstration of contractiledysfunction in papillary muscles isolated from cats with heartfailure secondary to pressure overload.9

Subsequently, the contractile process in failing heart mus-cle has undergone ever closer scrutiny. A defect in sarcomereshortening has been found in myocytes isolated from multiple

animal models,10 as well as from patients with advanced heartfailure.10,11 Moreover, reversibility of this defect through“unloading” the failing heart by placing the patient on aventricular assist device for several months has been demon-strated.11 This intriguing observation suggests that it may bepossible, as a therapeutic strategy, to reverse a process thathad long been considered to be irreversible and amenableonly to palliative therapy. As a consequence, left ventricularassist devices currently used as “bridges to heart transplan-tation” may become “bridges to recovery.”12 Perhaps evenmore exciting is the recent realization that the intrinsicdefects in myocardial contractile function present in somepatients with chronic heart failure may be partially reversedby medical therapy.13,14 That is, treatment of patients withchronic systolic heart failure withb-adrenergic blockingagents added to background therapy with ACE inhibitorsimproves systolic function and may reverse remodeling,13

leading to improved clinical outcomes, including prolongedsurvival and reduced hospitalizations.14 Thus, the view ofchronic myocardial failure as an irreversible, end-stage pro-cess is being supplanted by the idea that it is possible to effecttrue biologically based improvement in the intrinsic defectsof function and structure that afflict the chronically failingheart.

Abnormalities in Energy MetabolismThe cellular and molecular bases of heart failure havereceived considerable attention during the past half centuryand are under continuing active study. Although there is nosingle unifying pathogenetic theory, a number of biochemicalabnormalities have been described in heart failure. There isagreement that the efficiency of the heart as a pump isreduced in the low-output, systolic heart failure that occurs inischemic heart disease and dilated cardiomyopathy. The“external work” performed by the left ventricle is depressed,whereas its energy consumption is normal or almost so.15

Thus, the dilated, failing heart is energy-inefficient. Second,alterations in cardiac energy metabolism are frequently ob-served in systolic heart failure. Relative ischemia of thesubendocardium occurs in ventricular hypertrophy and dila-tation.16 High-energy phosphate stores, especially creatinephosphate (CrP), are reduced, not only in heart failuresecondary to acute ischemia but in other forms as well.17–19

From the Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, Mass, and the Division of Cardiology,Department of Medicine, University of Colorado Health Sciences Center, Denver.

Correspondence to Eugene Braunwald, MD, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115.(Circulation. 2000;102:IV-14–IV-23.)© 2000 American Heart Association, Inc.

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CrP serves as a buffer maintaining high ATP concentra-tions and a high ATP/ADP ratio. It may also facilitate thetransfer of high-energy phosphates from their source inthe mitochondria to their principal sites of consumption at themyofibrils and in the sarcoplasmic reticulum. Mitochondrialabnormalities may reduce the availability of high-energyphosphate stores in failing myocardium, perhaps related tomitochondrial damage that is mediated by oxygen radicals orautoantibodies.20 Reductions in the activity of creatine kinase,the enzyme that catalyzes the transfer of high-energy phos-phate stores from CrP to ADP to generate ATP, have beenreported in many forms of heart failure.21 Reduced activity ofthis enzyme intensifies the energy deficit in heart failure. Ifsevere enough, the resulting reduction in the free energy ofATP both slows the pump responsible for Ca21 uptake by thesarcoplasmic reticulum required for myocardial relaxation22

and impairs myofilament cross-bridge cycling, which is thebasis of cardiac contraction. These observations, first ob-tained in experimental models, have been extended to patientswith dilated cardiomyopathy by use of31P magnetic reso-nance spectroscopy. Importantly, a depressed CrP/ATP ratioin these patients has been found to be an independent,powerful predictor of early death.23

Altered Expression or Function ofContractile ProteinsThere is considerable evidence for changes in sarcomericproteins in the failing human heart24–29 (Table 1). The datainclude changes in the gene24,25 and protein26 expression ofmyosin heavy chain isoforms and alterations in the expres-sion of troponin T27 and in the isoform expression of myosinlight chain-1.28,29 In each case, the altered gene and proteinexpression most likely represents an induction of a “fetal”pattern of gene expression, whereby certain contractile,calcium-handling, and counterregulatory proteins revert tothe mRNA and protein expression pattern that characterizes

the fetal stage of development. Although this paradigm wasfirst observed in rodent myocardium,30,31it is now abundantlyclear that the same type of gene reprogramming also occurs inthe failing, hypertrophied human heart.24–26 In the case offetal expression patterns of thick- and thin-filament contrac-tile proteins, some of the alterations (myosin heavy chain,troponin T) reduce, while at least one (myosin light chain-1)increases, myofibrillar ATPase activity and/or contractilefunction. The net effect appears to be a reduction in myofi-brillar ATPase activity32 and contraction velocity, perhapsbecause the dominant changes are in myosin heavy chainisoforms. Although in animal models this reduction in veloc-ity of shortening was originally interpreted as being anadaptive, energetically favorable change,33 the end result is anincrease in wall stress and maladaptive neurohormonal/cytokine activation (see below) secondary to the reduction instroke volume and increase in ventricular volume. Thus,activation of harmful hypertrophy signaling pathways may bethe biggest outcome of a reversion to fetal gene expression.

A number of inherited cardiomyopathies may be related tomutations of genes encoding sarcomeric proteins. Familialhypertrophic cardiomyopathy, which causes impaired fillingand diastolic heart failure (and less commonly and in latecases, a dilated phenotype with systolic heart failure), iscaused by mutations in the genes encoding sarcomeric pro-teins. These include components of the thick filaments(cardiac b-myosin heavy chain and myosin light chains),components of the thin filaments (cardiac troponin T, tropo-nin I, anda-tropomyosin), and cardiac myosin-binding pro-tein C.34 All of these mutations probably produce abnormal-ities of force generation, which then incite a hypertrophicresponse.35 Dilated cardiomyopathy causing systolic heartfailure may result from mutations in genes encoding actin,36

which appear to produce an abnormality of force generationor transmission similar to genetic defects in cytoskeletalproteins, which are also associated with dilated cardiomyop-athy (see below).

Abnormalities of Excitation-Contraction Coupling:Diastolic Heart FailureAbnormalities of excitation-contraction coupling occur inmany forms of heart failure. Calcium ions (Ca21) play acentral role in both cardiac contraction and relaxation, and anumber of abnormalities of receptors, pumps, and proteinsresponsible for the transsarcolemmal and intracellular move-ments of Ca21 have been described in the failing human heart.In end-stage human myocardial failure, the result of thesechanges appears to be a prolongation of the Ca21 transient37

and an increase in diastolic Ca21 concentration.38 Thesechanges, probably caused by an impairment in the proteinexpression39 or function40 of sarcoplasmic reticular ATPase(SERCA-2a), would be expected to impair both diastolic andsystolic function.

Diastolic dysfunction secondary to impaired myocardialrelaxation and/or ventricular filling is associated with manycases of systolic dysfunction, but it is the primary cause of theclinical syndrome of heart failure in as many as one third ofall cases. Impaired cardiac filling may be caused by structuralabnormalities, eg, pericardial constriction or increased inter-

TABLE 1. Signals and Signal Transduction Pathways ThatMediate Pathological Hypertrophy in Model Systems

Signal/Type Signal Transduction System

Stretch/wall stress (mechanicaldeformation)

Gq/PLC/PKC, sarcolemmal ionchannels

Angiotensin II(autocrine/paracrine or hormone)

AT1 receptor–Gq/PKCb, –TKpathways, –MAPK pathways,JAK/STAT pathways, other

Norepinephrine (neurotransmitter) a-, b-Adrenergic pathways;oxidative stress pathways

Endothelin (paracrine) ETA receptor–Gq/PKCb pathway,calcineurin, and CAMK pathways

Ca21 (intracellular signal) CAM kinase pathway, calcineurinpathway

TNF-a (autocrine/paracrine) TNF receptors, MAPK, PKC

IL-1b (paracrine) IL-1 receptors, MAPK, TKpathways

Cardiotrophin-1(autocrine/paracrine)

Gp 130 pathways

PLC indicates phospholipase C; AT1, angiotensin type 1; MAPK, mitogen-activated protein kinase; and PKC, protein kinase C.

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stitial fibrosis; by physiological abnormalities, eg, abbrevia-tion of diastole, as occurs in tachycardia; and by abnormali-ties in myocyte relaxation, such as decreased activity orprotein expression of the SERCA-2a. Relatively low levels ofexpression of the transsarcolemmal Na1-Ca21 transporter canhave a similar effect by reducing Ca21 elimination frommyocytes.41 In addition, the aforementioned reduction ofmyofibrillar ATPase activity resulting from isoform shifts ofcontractile or regulatory proteins may prolong cross-bridgeattachment between actin and myosin and thereby impairmyocardial relaxation.

Cytoskeletal AbnormalitiesThe cardiac myocyte cytoskeleton is now known to be able toinfluence myocardial function dynamically, particularly inthe setting of pressure overload, in which excessive microtu-bular polymerization has been shown to adversely affectsystolic function.42 In addition, the concentrations of a num-ber of cytoskeletal proteins, such as desmin, tubulin, vinculin,dystrophin, talin, and spectrin, appear to be increased inend-stage failing human hearts.43 Conversely, the sarcomericskeletal proteinsa-actinin, titin, and myomesin may bedecreased in end-stage failing human hearts,43 and in a singlepatient with an idiopathic dilated cardiomyopathy, a completeabsence of metavinculin has been reported.44 These changesmay interfere with normal myocyte function and cause orcontribute to cell and chamber remodeling.

An impressively increasing number of cytoskeletal genemutations have been shown to be the basis for dilatedcardiomyopathy phenotypes.45 At the moment, the list inhumans includes dystrophin,45 desmin,46 sarcoglycans,47 andthe nuclear-envelope proteins lamin A and C.48,49The strain-specific model of heart failure/cardiomyopathy in the Syriangolden hamster has been shown to be due to a mutation in thed-sarcoglycan gene.50 In animals, genetic ablation of thecytoskeleton-associated muscle LIM protein (MLP) producesa useful model of dilated cardiomyopathy.51 It has beenreported that MLP expression is reduced in the failing leftventricular myocardium of patients with dilated and ischemiccardiomyopathy.52 Because MLP is important for the regula-tion of the cytoarchitecture of cardiac myocytes, reducedMLP content could be responsible for the impaired systolicfunction in ischemic or idiopathic dilated cardiomyopathy.53

Thus, mutations in various genes encoding cytoskeletal pro-teins appear to lead to the idiopathic dilated cardiomyopathyphenotype, suggesting that altered expression of this class ofproteins might have a role in the development of acquired(secondary) dilated cardiomyopathies as well.

Alterations in b-Adrenergic ReceptorSignal TransductionAn alteration inb-receptor signal transduction, downregula-tion of b1-adrenergic receptors, was one of the first candidatesproposed for a molecular defect in the failing humanheart.54,55 Multiple alterations inb-receptor signal transduc-tion have been described in the failing human heart, and thereis little doubt that they reduce cardiac reserve and contributeto decreased exercise responses in patients with chronic heartfailure.55 As originally conceived, changes inb-receptor

signal transduction were viewed as partially adaptivechanges, serving the useful purpose of withdrawing thecardiac myocyte from harmful adrenergic stimulation.55 Withthe recent recognition thatb-adrenergic receptors may pos-sess intrinsic activity and exist in an activated state even inthe absence of agonists, the idea has emerged that the loss ofb-receptor signal transduction can directly reduce intrinsicmyocardial function, that is, function in the absence ofcatecholamine agonists.56 However, at this point there is noevidence that this can occur in the failing human heart,inasmuch as dynamic changes in myocardial function can bedissociated from changes in intrinsicb-receptor signaltransduction.57

Ventricular Hypertrophy and RemodelingCardiac Myocyte HypertrophyMost types of myocardial failure are preceded by cell andchamber hypertrophy. The development of myocardial hyper-trophy initially represents an important adaptive mechanismto hemodynamic stresses.9 The initial functional benefits ofthe hypertrophic response include an increase in the numberof contractile elements, a lowering of wall stress throughincreased wall thickness in concentric hypertrophy, andincreasing stroke volume by increasing end-diastolic volumein eccentric hypertrophy.8 The hypertrophic process is char-acterized by structural changes at the cardiac myocyte levelthat are translated into alterations in chamber size andgeometry,58 collectively called remodeling. In addition tocardiac myocytes, other myocardial cells, such as fibroblasts,and increased production of extracellular matrix participate inthe remodeling process. In pressure-overload hypertrophy,additional sarcomeres are assembled in parallel, leading tothicker myocytes, to a concentric pattern of ventricularhypertrophy, and initially to well-maintained systolic func-tion. In contrast, in volume overload, additional sarcomeresare assembled in series, leading to longer myocytes, ventric-ular dilatation, and earlier dysfunction.

As listed in Table 1, numerous signaling pathways havebeen shown to induce cardiac myocyte and myocardialchamber hypertrophy. Most, if not all, the signaling pathwayslisted in Table 1 produce pathological hypertrophy, that is,hypertrophy accompanied by contractile dysfunction andpoor clinical outcomes. Increased hemodynamic stress (eitherpressure or volume overload) appears to be sensed bymyocytes, leading to changes in myocardial gene expression.It has been proposed that mechanical deformation activatessarcolemmal ion channels and is also transmitted to thenuclear membrane by the cytoskeleton.59 Intracellular [Ca21]is a regulator of myocyte hypertrophy, in part through apathway involving calcineurin, a Ca21-sensitive phospha-tase,60 which can be blocked by cyclosporin A.60,61 Thispathway and the calmodulin kinase pathway are both acti-vated by increases in intracellular [Ca21], and both may beinvolved in hypertrophic responses resulting from abnormal-ities in Ca21 handling mechanisms or in response toneurohormonal-cytokine signaling.62

Neurohormonal and autocrine/paracrine mediators of hy-pertrophy include norepinephrine (viaa- or b-receptor path-

IV-16 Circulation November 14, 2000



ways), angiotensin II, endothelin 1, fibroblast growth factor,transforming growth factor-b1, the proinflammatory cyto-kines tumor necrosis factor-a (TNF-a) and interleukin-1b(IL-1b), and G protein 130–signaling cytokines. These ago-nists transmit their signals through signal transduction pro-teins (such as ras, Gaq, and Gas) to activate a family ofenzymes (such as protein kinase C [PKC], mitogen-activatedprotein kinases, and Raf-1 kinases) that induce the fetal geneprogram. Activation of G-coupled isoforms of PKC stimu-lates hypertrophy, which can lead to a fibrotic cardiomyop-athy,63,64 and PKC-b isoforms are upregulated in the failinghuman heart.65

The molecular signature of pathological hypertrophy isfetal gene induction, including changes in gene expression ofcontractile proteins and calcium handling that interfere withcontractile function. Thus, hypertrophy is not simply a matterof a quantitative increase in contractile proteins and other keyelements that initiate and regulate contraction, but rather, it isalso associated with qualitative changes in gene expressionthat lead to an impairment of contractile function. A list ofgenes considered to be part of the human fetal program thatis reinduced in hypertrophy is given in Table 2.

The precise mechanism(s) responsible for the transitionfrom adaptive hypertrophy to maladaptive heart failure areelusive, but there are several candidate mechanisms. Inaddition to deficiencies in high-energy phosphate stores anddefects in excitation-contraction coupling, excess formationof myocyte microtubules, which impairs sarcomere shorten-ing, may be involved.42 On the basis of work done in animalmodels30,31 and humans,24–26 induction of the contractileprotein fetal gene program to the point where contractilefunction is severely impaired is a viable candidate, as is thedevelopment of Ca21-handling abnormalities that are partof66,67or separate from39 fetal gene induction. Attenuation, orin some cases even total loss, ofb-adrenergic signal trans-duction as the major means of supporting decreased myocar-dial performance probably contributes to the transition aswell.68 Other possibilities include ultrastructural disorganiza-tion of cytoskeletal proteins and the development of extensiveinterstitial myocardial fibrosis. Finally, apoptosis (see below)could be a key component of myocardial decompensation incertain settings.

Relationship Between Myocardial ContractileDysfunction and Hypertrophy/Remodeling

An extremely important concept that has emerged in recentyears is the close connection between remodeling and con-tractile dysfunction. These are the 2 most important patho-physiological processes in the failing heart, and as depicted inFigure 1, they are intimately interrelated. That is, if cardiacmyocyte or myocardial contractile dysfunction is initiallypresent, numerous hypertrophy signaling pathways that ulti-mately lead to remodeling will be activated. Conversely, ifremodeling without contractile dysfunction is initiallypresent, as has been demonstrated in some animal models,69

contractile dysfunction will follow. This may be due to any ofseveral processes that include energetic stress,70 altered Ca21

handling,71 and induction of the fetal gene program. Con-versely, any type of therapy that interrupts this positivefeedback cycle will attenuate or reverse the progression ofmyocardial function and remodeling.13

Extracellular MatrixHypertrophied and failing hearts usually exhibit considerableinterstitial fibrosis, which stiffens the ventricles and impedesboth contraction and relaxation. An increased expression of anumber of extracellular matrix proteins, including severalforms of collagen and fibronectin, has been described. Matrixmetalloproteinases (MMPs) and their inhibitors (TIMPs) areintimately involved in the remodeling of the cardiac matrix.Enhanced expression of MMPs and reduced expression ofTIMPs have been described in heart failure, and the applica-tion of an inhibitor has been shown to retard experimentallyproduced heart failure.72

TABLE 2. Fetal Gene Program Induction in Hypertrophied, Failing Human Ventricular Myocardium, Degreeof Expression 0–41

Gene Expressed Adult Pattern Fetal Pattern Hypertrophy/Failure Biologic Effect in Hypertrophy

a-MyHC 11 0–1 0–1 2 Contractile function

b-MyHC 111 1111 1111 2 Contractile function

1 Cell growth

SERCA 111 11 11 2 Contractile function

Natriuretic peptides (ANP, BNP) 0–1 111 111 ? 2 Cell growth

Skeletal actin 111 1111 ? z z z

Cardiac actin 1 0–1 ? z z z

MyHC indicates myosin heavy chain; SERCA, sarcoplasmic reticular ATPase; ANP, atrial natriuretic peptide; and BNP, brainnatriuretic peptide.

Figure 1. Relationship between progressive myocardial dysfunc-tion and remodeling. From: Bristow MR. Management of heartfailure. In: Braunwald E, Zipes D, Libby P, eds. Heart Disease.6th ed. Philadelphia, Pa: WB Saunders; In press.




Cardiac Myocyte ApoptosisA recently emphasized and probably important component ofthe remodeling process and of the transition from adaptivehypertrophy to heart failure is cardiac myocyte apoptosis, orprogrammed cell death.73,74 This precisely orchestrated ge-netic program is stimulated by a variety of factors, includinghypoxia; enhanced activity of G-coupled proteins throughactivation ofb- and a-adrenergic receptors, angiotensin II,and TNF-a (see below); mitochondrial injury; myocyte Ca21

overload; cell injury of diverse causes, including O2-derivedfree radicals; activation of certain sarcolemmal receptors (Fasreceptors); and the action of a class of specific proteases, thecaspases. The latter degrade target proteins in the nucleus,cytoskeleton, and mitochondria. Stretching of sarcomeres invitro results in the release of angiotensin II from cardiac cells,which triggers myocyte apoptosis. ACE inhibition can pre-vent this form of cell death in vivo.75

Pacing-induced heart failure has served as a useful exper-imental model for the study of idiopathic dilated cardiomy-opathy.18 This form of heart failure has been found to beassociated with enhanced expression of Bax, a gene thatstimulates apoptosis, and with attenuation of the expressionof a proto-oncogene, Bal-2, which protects against apoptosis.These changes in gene expression may be caused by theactivation of the tumor suppressor gene p53.75 The myocar-dial apoptosis that occurs during aging and that is acceleratedin overloaded cells increases the burden on surviving myo-cytes and hastens their death, thereby setting up a viciouscircle. In experimental preparations, marked reductions inapoptosis have been found withb-adrenergic blockade, ACEinhibition, and blockade of the angiotensin II type I recep-tor.74 Although its role in less advanced forms of humanmyocardial failure is uncertain, cardiac myocyte apoptosishas been clearly demonstrated in end-stage failing humanhearts.76 Thus, as shown in Figure 2, cell loss via apoptosis ornecrosis joins altered expression of genes regulating contrac-

tility as 2 fundamental processes that can produce progressivemyocardial dysfunction in the failing human heart.

Neurohormonal-Cytokine ChangesStudies in the early 1960s demonstrated the presence ofincreased concentrations of circulating norepinephrine77 andreduced cardiac content of norepinephrine in patients withheart failure.78 A large number of investigations on neuro-hormonal changes in heart failure followed. It is now clearthat in conditions characterized by a reduction of cardiacoutput and/or an increase in wall stress, a number of neuro-hormonal systems, notably the adrenergic system, the renin-angiotensin-aldosterone system (RAAS), and thehypothalamic-neurohypophyseal system are activated. Also,there is release of endothelin from the vascular bed. Theactivation of these systems initially serves to maintain arterialpressure and thereby coronary and cerebral perfusion pres-sures. Blood volume is conserved in the presence of hypovo-lemia or is expanded in the case of heart failure; the latterenhances contraction of the acutely failing ventricle byallowing it to move up on its Starling curve.

Whereas activation of these systems is clearly adaptiveover the short term in acute heart failure and hypovolemicshock, it became clear in the 1980s that persistent activationis maladaptive in chronic heart failure. Thus, continuedactivation of the adrenergic system increases ventricularafterload and therefore the hemodynamic burden placed onthe failing ventricle. At the same time, activation of thissystem contributes to an increase in heart rate and myocardialenergy costs; it may cause hypertrophy, ischemia, and tachy-arrhythmias and damage myocytes further, perhaps throughmyocardial Ca21 overload or apoptosis.74 At the myocardiallevel, there is ample evidence of overactivity of adrenergicdrive. The original observation in failing human hearts wasthat cardiac content of the adrenergic neurotransmitter nor-epinephrine was reduced or depleted.78 We now know thatthis tissue-store depletion is the result of sustained increasedrelease and decreased reuptake of neurotransmitter,79,80 re-sulting in a constant exposure to levels of norepinephrine thatare almost certainly cardiotoxic.14,55 Chronic b-adrenergicstimulation has been shown to induce expression of theproinflammatory cytokines TNF-a, IL-1, and IL-6,81 whichmay impair cardiac contraction, promote chamber enlarge-ment, and thus play a significant role in the development of adilated cardiomyopathy phenotype. The reaction of the heartto this maladaptive signaling is easily measured; in explanted,severely failing human hearts, the density ofb1-adrenergicreceptors, the G protein coupling of bothb1- andb2-receptors,b-adrenergic stimulation of the activity of the enzyme adeny-lyl cyclase, and in some studies the intracellular concentrationof cAMP are all reduced.14,55,68 Phosphorylation ofb1-receptors by theb-adrenergic receptor kinase-1, an enzymethat is increased in heart failure, has been shown to be animportant mechanism for desensitization of these receptors.82

Activation of b1-receptors through a cAMP-dependent ki-nase, PKA, causes the phosphorylation of phospholamban, aprotein that in its unphosphorylated state inhibits the uptake(and release) of Ca21 by the SERCA-2a. Phosphorylation ofphospholamban enhances the uptake of Ca21 from the cyto-

Figure 2. Vicious circles that operate in the presence of myo-cardial damage leading to dysfunction. A cascade of eventsleads to altered gene expression and/or cell death, both ofwhich impair myocardial function further. From: Bristow MR.Management of heart failure. In: Braunwald E, Zipes D, Libby P,eds. Heart Disease. 6th ed. Philadelphia, Pa: WB Saunders; Inpress.




plasm. Loss of theb-adrenergic mechanism in heart failureleaves phospholamban in the unphosphorylated state, therebyimpairing Ca21 movements and interfering with cardiaccontraction and relaxation.83 In addition, genetic variants ofb-adrenergic receptors may be associated with rapid progres-sion of heart failure.84,85

In the severely failing heart, acute blockade ofb-adrenergic receptors can remove hemodynamically impor-tant b-adrenergic support and may thereby intensify heartfailure. Gradual escalation of the dose of orally administeredb-adrenergic blockers, however, has been shown to be ofsubstantial clinical benefit,86–88andb-blocker therapy is nowrecommended for all but the most advanced cases of symp-tomatic chronic systolic heart failure.14 The myocardial func-tional effects of chronicb-blockade are in fact diametricallyopposite to the acute effects, because long-term ($3 months)blockade is associated with improved intrinsic systolic func-tion and decreased ventricular volumes.13 These salutaryeffects on myocardial function and structure are most likelyresponsible for the majority of the clinical benefits producedby b-blocking agents, which include a substantial reductionin mortality and a reduction in heart failure–related hospital-izations in chronic heart failure.14

Heart failure is also characterized by elevated circulatingand tissue concentrations of angiotensin II, a vasoconstrictorthat increases ventricular afterload and causes myocyte hy-pertrophy, apoptosis, interstitial fibrosis, cardiac and vascularremodeling, and the secretion of aldosterone. The latter alsoplays an important role in cardiac remodeling, the prolifera-tion of fibroblasts, and the deposition of collagen.89 Thesechanges increase the passive stiffness of the ventricles and thearterial bed, interfere with ventricular filling, and reducearterial compliance.90 Elevated concentrations of circulatingaldosterone are predictive of adverse outcome in heart failurepatients.91 Inhibitors of the RAAS, ie, ACE inhibitors, angio-tensin receptor blockers, and aldosterone inhibitors, have allbeen found to exert salutary effects in the treatment of heartfailure. Indeed, ACE inhibitors are now considered to be acornerstone in the management of most forms of heart failureand many forms of cardiac hypertrophy.

There is increasing evidence of cross talk between theadrenergic system and the RAAS. Thus, in patients with heartfailure, ACE inhibition has been found to reduce the en-hanced peripheral sympathetic nerve impulse traffic92 andcardiac adrenergic drive,93 and the beneficial effects of ACEinhibitors appear to be especially prominent in patients withadrenergic activation.94 Aldosterone reduces the neuronalreuptake of norepinephrine and thereby enhances cardiacarrhythmias.95 Heart failure patients who are already receiv-ing an ACE inhibitor and a diuretic and who have normalrenal function receive a substantial mortality benefit from theadministration of spironolactone.96 Eplerenone, a new spe-cific aldosterone antagonist97 that does not have the adverseeffects of spironolactone, such as gynecomastia, is now beingtested.

Arginine vasopressin (AVP) is synthesized in the hypo-thalamus and then stored and released from the neurohypoph-ysis; its release is enhanced by osmolar stimuli as well aselevated concentrations of norepinephrine and angiotensin II.

Increased release of AVP in heart failure causes vasoconstric-tion (through binding to V1 receptors), water retention, anddilutional hyponatremia. Multiple signaling molecules, in-cluding angiotensin II, norepinephrine, AVP, and IL-1, allstimulate the production of endothelin, which, by activatingendothelin A receptors, constricts vascular smooth muscle.The concentration of circulating endothelin is an importantpredictor of outcome in heart failure,98 and endothelin growthpathways are likely to be important determinants of patho-logical remodeling.99

The benefits of blocking neurohormonal activation in heartfailure extend to endothelin and AVP. Blockade of receptorsto these agonists has been shown to be efficacious in patientsand experimental models of heart failure.100–102 Althoughthese agents have not yet been approved for clinical use, theyrepresent a promising area for future development.

Vascular endothelium also produces the potent vasodilatornitric oxide (NO), but the response to this substance isreduced in heart failure,103 contributing to the vasoconstric-tion characteristic of this condition.

Proinflammatory CytokinesIn addition to neurohormonal activation, a number of proin-flammatory cytokines, including TNF-a and IL-1b, are over-expressed in the failing heart.104 TNF-a is also increased inthe systemic circulation.105 TNF-a is produced as a conse-quence of volume overload and evokes both systemic andlocal (cardiac) inflammatory responses. The former includethe cachexia and skeletal muscle myopathy characteristic ofheart failure,105 and the latter cause myocardial inflammation,cell proliferation, and apoptosis, thereby causing or intensi-fying heart failure.104,106 Transgenic mice that overexpressTNF-a exhibit myocarditis, heart failure, and shortenedsurvival.107,108 TNF-a also activates transcription factors aswell as enzymes involved in signal transduction and inducesa number of genes, including the fetal gene program andthose that encode growth factors, receptors, and heat-shockproteins.109Release in the heart of TNF-a and other cytokinesmay activate inducible NO synthase, an enzyme that en-hances the production of NO, a substance that may impairmyocardial function. The infusion of soluble receptors forTNF-a blocks its action on the heart and improves thedepressed ventricular function in rats infused with the cyto-kine.106 Early studies with this receptor in patients with heartfailure are promising.110 Myocardial TNF-a content has beenshown to be reduced by chronic ventricular unloading with aleft ventricular assist device,111 and this may play a role in thereversal of myocardial failure referred to earlier.11

Figure 3 displays, in simplified form, current ideas of theinterplay between cardiac function and neurohormonal-cytokine systems. The impairment of cardiac function causedby myocardial injury activates these systems, many of whichconfer a beneficial response in acute heart failure. However,their chronic activation causes additional myocardial injuryand depresses cardiac function further. By causing myocytehypertrophy and apoptosis, as well as remodeling and fibrosisof the ventricles, they set up a series of vicious circles.Fortunately, many of these maladaptive processes can now beblocked, thereby preventing or interrupting these circles.




Indeed, blockade of the activated neurohormonal systemswith b-adrenergic blockers, ACE inhibitors, angiotensin typeI receptor blockers, and aldosterone antagonists is a keycomponent of the contemporary management of heart failure.

The vasodilator peptides, such as atrial natriuretic peptideand brain natriuretic peptide, which are elaborated by dilatedatria and ventricles, are also overexpressed in chronic heartfailure, but in contrast to the aforementioned neurohormonalsystems, they exert a counterregulatory or beneficial effect.By acting on specific receptors in vascular smooth muscleand the kidneys, they cause vasodilation, enhanced sodiumexcretion, and reduced secretion of renin and aldosterone.Drugs that prevent metabolism of these peptides, so-calledneutral-endopeptidase inhibitors, especially when they arecombined with an ACE inhibitor in a single molecule,so-called vasopeptidase inhibitors, appear to be promising.112

Ischemic Heart FailureIt has been known for more than a century that myocardialischemia can cause acute heart failure and that chronicischemic heart disease can cause chronic heart failure. How-ever, it has become appreciated only relatively recently thatwhen severe, prolonged myocardial ischemia is relieved, therecovery of cardiac function is not immediate, but mayrequire hours,113 days, or even weeks; this phenomenon hasbeen called myocardial stunning.114 Repetitive episodes ofischemia caused by increases in myocardial oxygen require-ments in the presence of a fixed oxygen supply can causechronic stunning, which is characterized by persistent impair-ment of cardiac function. In myocardial hibernation, a pro-cess closely related to chronic stunning, myocardial functionis downregulated to match a chronic reduction in coronaryblood flow.115 Whatever the responsible mechanism(s),chronic stunning and hibernation are characterized by viablemyocardium that fails to contract normally, and when this

contractile defect involves a large enough portion of the leftventricle, it may cause heart failure. Coronary revasculariza-tion has been shown to restore function in the chronicallyischemic myocardium and thereby reduce heart failure andprolong survival.116 Indeed, the restoration of function ofchronically ischemic myocardium by revascularization hasemerged as an important approach to reversing heart failure.

ConclusionsDuring the past half century, both the causes and treatment ofheart failure have changed considerably. Hypertensive andvalvular heart diseases were the most frequent causes of heartfailure in the United States and other Western nations in1950. Now, ischemic heart disease, hypertensive heart dis-ease, and idiopathic dilated cardiomyopathy are dominant.The treatment of heart failure in 1950 consisted of bed rest, adiet restricted in sodium, the inotropic agent digitalis, andparenterally administered diuretics. Today, physical activityis encouraged, and drugs that block neurohormonal activationare widely used. Powerful oral diuretics are available, and forend-stage heart failure, left ventricular assist devices andtransplantation may be lifesaving. Digitalis is still used insystolic heart failure, but it plays a secondary role exceptwhen atrial fibrillation is present. Ventricular fibrillation, aleading cause of death in heart failure, can now be preventedin many cases with an internal cardioverter-defibrillator.

Despite the enormous advances in the understanding andtreatment of heart failure that have taken place during the 50years since the birth ofCirculationand that have been so welldescribed in this journal, this condition remains a serious, andin fact, a growing problem in the United States and world-wide. It has been estimated that there are 4.6 million patientsin the United States with heart failure and perhaps an equalnumber with asymptomatic left ventricular dysfunction whoare at high risk of developing heart failure. This condition isthe primary discharge diagnosis in almost 1 million patientsfrom US hospitals annually, and an estimated 550 000 newcases occur each year. Prognosis is poor, with mediansurvival after onset only 1.7 years in men and 3.2 years inwomen.117 Heart failure is a condition that affects principallythe elderly, and with the progressive aging of the population,it is virtually certain that the prevalence of heart failure willcontinue to grow during the next decade both in developedand in developing nations.

What accounts for the seeming paradox of the greatlyimproved management of virtually all forms of heart diseasethat lead to heart failure and the increasing occurrence ofheart failure? Many forms of heart disease that can now besuccessfully treated are not really cured. For example, thetreatment of severe hypertension may avert premature deathfrom a cerebrovascular hemorrhage. However, antihyperten-sive therapy often converts severe to mild hypertension; thelatter, acting over many years, can cause left ventricularhypertrophy and ultimately lead to heart failure. Similarly,the prolongation of survival after acute myocardial infarctionby acute reperfusion may be associated with substantialmyocardial damage that subsequently causes heart failure viathe remodeling process or with subsequent ischemic damage.Progressive myocyte loss is a feature of aging,118 and when

Figure 3. Interplay between cardiac function and neurohumoraland cytokine systems. Myocardial injury of many causes candepress cardiac function, which in turn causes activation ofsympathoadrenal system (ANS) and RAAS and elaboration ofendothelin, AVP, and cytokines such as TNF-a. In acute heartfailure (left), these are adaptive and tend to maintain arterialpressure and cardiac function. In chronic heart failure (right),they cause maladaptive hypertrophic remodeling and apoptosis,which cause further myocardial injury and impairment of cardiacfunction. Horizontal line on right (*) shows that chronic maladap-tive influences can be inhibited by ACE inhibitors, b-adrenergic(badren) blockers, angiotensin type 1 (AT1) receptor blockers,aldosterone (aldo) antagonists, and endothelin type A (ETA)blockers.




additional cardiac damage, be it secondary to chronic hemo-dynamic overload or ischemia, is superimposed on an agingheart with a dwindling number of myocytes, the burden onthe remaining myocytes increases and the likelihood of heartfailure rises. Finally, on the basis of estimates of the propor-tion of eligible patients with heart failure, only a minority arereceiving both ACE inhibitors andb-blocking agents, the 2major classes of agents for which databases from multipleclinical trials have consistently and unequivocally demon-strated reductions in mortality and delayed progression of theheart failure syndrome.14 In other words, although muchprogress has been made in heart failure clinical trials (a 46%reduction in mortality in the last 10 years14), this has not beentranslated optimally into clinical practice. The reasons for thisare complex, but this mismatch between the ideal and theactual must be corrected if the heart failure problem is to besolved.

Future scientific progress in heart failure is likely to take 4principal directions. Most important of all will be the preven-tion of atherosclerotic heart disease, the most common causeof heart failure. Prevention is likely to commence muchearlier in life, when genetic analysis makes it possible toidentify persons with a high likelihood of developing a riskfactor for atherosclerosis later in life. A second type ofadvance will be the extension of current efforts to inhibit theactivated neurohormonal-cytokine systems in heart failure.As discussed above, blockade of endothelin, of AVP, ofcytokines, including TNF-a, and of the breakdown of natri-uretic peptides all appear to be promising. Third, both cardiacunloading with long-term ventricular assistance and replace-ment of the heart with a totally implanted mechanical deviceor xenotransplant have the potential to prolong life greatly inpatients with heart failure. Further on the horizon, new agentsdesigned to modulate novel therapeutic targets and/or genetherapy may become useful as we learn more about themolecular defects in various types of myocardial failure.Therefore, we predict with confidence that in 2025, when theAmerican Heart Association celebrates 75 years of publica-tion of its flagship journal,Circulation, understanding of themechanisms responsible for heart failure will have increasedenormously, therapy will be greatly enhanced, and the prev-alence of the condition will have peaked and be on thedecline.

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KEY WORDS: angiotensinn cardiomyopathyn edema n endothelin nheart failure




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Congestive Heart Failure: Fifty Years of Progress